Method for stereochemically controlled production of isomerically pure highly substituted azacyclic compounds

ABSTRACT

A method for stereochemically controlled production of azacyclic compounds of general formula (I) 
                 
 
in which the substituents have the meanings given in the specification. The invention also relates to intermediate products of this method and to novel azacyclenes.

BACKGROUND OF THE INVENTION

The present invention relates to a novel process for thestereochemically controlled production of novel and known highlysubstituted azacyclic compounds and to novel intermediate products ofthis process. Furthermore, the invention relates to novel highlysubstituted azacyclic compounds which can be built up in isomericallypure manner and which have useful properties for numerous fields ofapplication.

Highly substituted stereoisomers of azacyclic compounds, in particularhighly substituted derivatives of pyrrolidines or piperidines, areuseful starting materials for numerous applications, and are used, forexample, as constituents of chiral catalysts in asymmetrical synthesis(see, e.g., Kobayashi et al., Chemistry Letters (=Chem. Lett.) (1991)1341-1344), as constituents of biologically active alkaloids (see, e.g.,Williams et al., Journal of Organic Chemistry (=JOC) 57 (1992) 6527-6532and references cited therein; Jäger et al., Angewandte Chemie 102 (1990)1180-1182) and as constituents of pharmacologically interestingcompounds (see, e.g., Laschat et al., Synthesis 4 (1997) 475479).Furthermore, for example decahydroquinolines and pyrrolidines which canbe produced according to the process of the invention or ones which arestructurally closely related have interesting physiological effects(see, e.g., Kuzmitskii et al., Vestsi Akad. Navuk BSSR, Ser. Khim. Navuk3 (1979) 82-85/Chemical Abstracts No. 91:117158c; Lash et al., Journalof Heterocyclic Chemistry 28 (1991) 1671-1676). The use of some of thepyrrolidines mentioned above for the production of porphyrin ringsystems is also discussed therein. Processes for the production of suchazacyclic compounds are also known in part from the literature sourcesquoted. Certain enantiomers of these compounds may be obtained accordingto the methods referred to therein usually by means of conventionalracemate separation. However, production processes which are not inaccordance with the invention are also mentioned, according to whichselected individual compounds of substituted azacyclic compounds can beproduced in isomerically pure manner. A general process for thestereo-controlled synthesis of isomerically pure, highly substitutedazacyclic compounds is not known from the above literature sources.

Furthermore, the stereo-controlled synthesis of some tetrahydrofuranderivatives by reaction of 2-alkenyl sulfoximides with 2-tert.butyldimethyl-silyloxy-propanal (=TBS lactaldehyde) and subsequentfluoride-induced cyclisation is already known (see Reggelin et al., JACS118 (1996) 4765-4777; Reggelin et al., Liebigs Annalen derChemie/RECUEIL (1997) 1881-1886). However, highly substituted azacycliccompounds cannot be produced according to the process described therein.

The compound(2S,3S,4S,5S)-(N-tert.-butyloxycarbonyl)-2-benzyl-4,5-dimethyl-3-hydroxypyrrolidineis already known from the Internet publication at the address“www.iucr.ac.uk” by M. Bolte, Acta Crystallographica Section C,electronically published paper QA0017 [=(IUCr) Acta C Paper QA 0017].The production of this compound is not described in the publicationcited.

SUMMARY OF THE INVENTION

It was an object of the present invention to provide a process for thestereochemically controlled production of novel and known highlysubstituted azacyclic compounds with which the type and number ofsubstituents in these compounds can also be varied widely and which canbe built up in isomerically pure manner. Furthermore, it was an objectof the invention to provide novel, in particular isomerically pure,highly substituted azacyclic compounds for numerous fields ofapplication.

It has now surprisingly been discovered that highly substitutedazacyclic compounds in which the type and number of substituents can bevaried widely can be built up in a good yield in particular inisomerically pure manner if metalated 2-alkenyl sulfoximide compoundsare reacted according to a process of the invention with N-protected α-or β-aminoaldehydes which may have the substitution pattern given in thedescription in the α and/or β position.

The subject of the invention is thus a process for the stereochemicallycontrolled production of compounds of the general formula 1,

wherein

-   n is 0 or 1-   R¹ is hydrogen; C₁-C₆-alkyl; or phenyl-C₁-C₆-alkyl optionally    substituted one or more times in the phenyl ring by lower alkyl,    lower haloalkyl, lower alkoxy or lower haloalkoxy, and-   R² is hydrogen, or-   R¹ and R² together are a double-bonded methylene group which may be    substituted by C₁-C₅-alkyl or by phenyl-C₁-C₅-alkyl optionally    substituted one or more times in the phenyl ring by lower alkyl,    lower haloalkyl, lower alkoxy or lower haloalkoxy,-   R³ is hydrogen, and-   R⁴ is hydrogen; lower alkyl; or phenyl-lower alkyl optionally    substituted one or more times in the phenyl ring by lower alkyl,    lower haloalkyl, lower alkoxy or lower haloalkoxy, or-   R³ and R⁴ also together are a C₂-alkylene chain; or a C₃-C₆-alkylene    chain optionally containing 1 to 3 double bonds, which may be    bridged by C₁-C₂-alkylene which is optionally substituted one or two    times by lower alkyl,-   R⁵ is hydrogen; lower alkyl; hydroxy; lower alkoxy; phenyl-lower    alkoxy or phenyl-lower alkyl each of which may be optionally    substituted one or more times in the phenyl ring by lower alkyl,    lower haloalkyl, lower alkoxy or lower haloalkoxy, and-   R⁵ is hydrogen, and-   R⁷ is hydrogen, and-   R⁸ is hydrogen; cyano; optionally esterified carboxy; carbonylamino    optionally substituted one or two times at the nitrogen; a    monocyclic or bicyclic ring system with 3 to 10 ring carbon atoms    which is optionally unsaturated one or more times, the ring carbon    atoms of which may be replaced one or more times by nitrogen, oxygen    and/or sulfur and which ring system may be substituted one or more    times by lower alkyl, lower haloalkyl, lower alkoxy, hydroxy,    halogen or by a lower alkylene chain which is bonded to two oxygen    atoms bonded to adjacent carbon atoms of the ring system, or    -   also may stand for straight-chain or branched C₁-C₁₂-alkyl        optionally containing one or more double bonds which may be        substituted one or more times by halogen, hydroxy, lower alkoxy,        optionally esterified carboxy, cyano, mercapto, lower alkylthio,        amino, lower alkylamino, carbonylamino optionally substituted        one or two times at the nitrogen, a monocyclic or bicyclic ring        system with 3 to 10 ring carbon atoms which is optionally        unsaturated one or more times, the ring carbon atoms of which        may be replaced one or more times by nitrogen, oxygen and/or        sulfur and which ring system may be substituted one or more        times by lower alkyl, lower haloalkyl, lower alkoxy, hydroxy,        halogen or by a lower alkylene chain which is bonded to two        oxygen atoms bonded to adjacent carbon atoms of the ring system,        or-   R⁵ and R⁸ also, together with the carbon atoms to which they are    bonded, may form a monocyclic or bicyclic ring system with 5 to 10    ring carbon atoms which optionally contains 1 to 3 double bonds, the    carbon atoms of which which do not bear the substituents R⁵ or R⁸    may be replaced one or more times by sulfur, oxygen and/or nitrogen,    and which optionally may be substituted one or more times by lower    alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, hydroxy,    halogen or by a lower alkylene chain which is bonded to two oxygen    atoms bonded to adjacent carbon atoms of the ring system, or-   R⁶ and R⁷ also together may form a bond, and-   R⁵ and R⁸, together with the carbon atoms to which they are bonded,    may form an aromatic C₆-ring system which may be fused with 2 to 4    further carbon atoms to form a bicyclic ring system having a total    of 3 to 5 double bonds which contains a total of 8 to 10 ring carbon    atoms, wherein the carbon atoms of this C₆- to C₁₀-ring system which    do not bear the substituents R⁵ and R⁶ may be replaced one or more    times by sulfur, oxygen and/or nitrogen, and wherein this C₆- to    C₁₀-ring system may optionally be substituted one or more times by    lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy,    hydroxy, halogen or by a lower alkylene chain which is bonded to two    oxygen atoms bonded to adjacent carbon atoms of the ring system,-   R⁹ is hydrogen; lower alkyl; phenyl-lower alkyl optionally    substituted one or more times in the phenyl ring by lower alkyl,    lower haloalkyl, lower alkoxy or lower haloalkoxy; or an amino    protecting group, or-   R⁸ and R⁹ also together may form a C₃-C₄-alkylene chain, and-   Y is oxygen or NH,    and their acid addition salts, wherein any reactive groups which may    be present may be blocked in compounds of Formula I by suitable    protecting groups, characterized in that-   a) a compound of the general formula II,    wherein R³ and R⁴ have the above meanings, R¹⁰¹ has the meaning    given above for R¹ with the exception of an optionally substituted    methylene group, Ar stands for phenyl optionally substituted one or    more times by lower alkyl, R¹⁰ is lower alkyl, or phenyl optionally    substituted once in the phenyl ring by lower alkyl or by hydroxy    protected with a suitable protecting group, or phenyl-lower alkyl    optionally substituted once in the phenyl ring by lower alkyl, and    R¹¹⁰¹ stands for a silyl protecting group, is reacted in succession    with a base suitable for the deprotonation thereof, an    organometallic reagent of the general formula VII,    XM²(OR¹²)₃  VII-    wherein X stands for halogen, M² is a tetravalent transition metal    and R¹² stands for lower alkyl, phenyl or phenyl-lower alkyl, and a    stereoisomer of a compound of the general formula VIII,-    wherein R⁵, R⁶, R⁷ and n have the above meanings, R⁸⁰¹ has the    meaning of R⁶, with any reactive groups if necessary being blocked    by base-stable protecting groups, R⁹⁰¹ stands for hydrogen or    together with R⁸⁰¹ stands for a C₃-C₄-alkylene chain and R¹³ is an    amino protecting group which when cleaved leaves behind a nitrogen    nucleophile, to form a stereoisomer of a compound of the general    formula IX,-    wherein R¹⁰¹, R³, R⁴, R⁵, R⁸, R⁷, R⁸⁰¹, R⁹⁰¹, R¹⁰, R¹¹⁰¹, R¹², R¹³,    n, Ar and M² have the above meanings,-   b) the resulting compound of Formula IX is converted, by treatment    with a reagent suitable for removing the group R¹³, into a compound    of the general formula Xa,-    wherein R¹⁰¹, R³, R⁴, R⁵, R⁶, R⁷, R⁸⁰¹, R⁹⁰¹, R¹⁰, n and Ar have    the above meanings and R¹¹ stands for hydrogen or a silyl protecting    group and, if R⁹⁰¹ stands for hydrogen, the nitrogen atom in the    cyclic parent structure of the resulting compound of Formula Xa is    blocked with a base-stable protecting group and any silyl protecting    group R¹¹ which may still be present is cleaved off, and-   c) for the production of a compound of the general formula Ia,-    wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸⁰¹ and n have the above    meanings and R⁹⁰² stands for a base-stable protecting group or,    together with R⁸⁰¹′, for a C₃-C₄-alkylene chain,    -   ca) a resulting compound of Formula Xa or a compound produced by        cleaving off the silyl protecting group R¹¹ is reacted with a        reagent suitable for the reductive cleavage of the        sulfonimidoyl-alkyl bond, in order to obtain a compound of the        general formula Ib,    -    wherein R¹⁰¹, R³, R⁴, R⁵, R⁶, R⁷, R⁸⁰¹, R⁹⁰² and n have the        above meanings, or    -   cb) in a resulting compound of Formula Xa wherein R¹⁰¹ does not        stand for hydrogen, the sulfonimidoyl-alkyl bond is cleaved        after electrophilic activation of the sulfonimidoyl unit under        the conditions of a base-induced elimination, in order to obtain        a compound of the general formula Ic,    -    wherein R³, R⁴, R⁵, R⁶, R⁷, R⁸⁰¹, R⁹⁰² and n have the above        meanings and R¹⁰² stands for C₁-C₅-alkyl; or phenyl-lower alkyl        optionally substituted one or more times in the phenyl ring by        lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkoxy,        the lower alkylene chain of which phenyl-lower alkyl may contain        1 to 5 carbon atoms,        and a resulting compound of Formula Ia is reacted if desired one        or more times by reaction, in each case with inversion of the        configuration at the ring carbon atom in the 3-position of the        compounds of Formula Ia, with a nucleophilic reagent suitable        for regenerating an OH group or for generating an NH₂ group in        the 3-position, and/or if desired any protecting groups are        cleaved again in compounds of Formula Ia and if desired the        optionally released NH group in the 1-position of the cyclic        parent structure is reacted with a reagent capable of        N-alkylation or one capable of amide formation or is blocked        with an amino protecting group, in order to obtain compounds of        Formula I, and free compounds of Formula I if desired are        reacted to form acid addition salts, or acid addition salts of        compounds of Formula I are reacted to form free compounds.        Furthermore, the subject of the invention is novel azacyclic        compounds.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

If substituents in compounds of Formula I or in other compoundsdescribed within the scope of the present invention are or contain loweralkyl, this may be branched or unbranched, and usually contain 1 to 4carbon atoms.

If substituent constituents, for example radicals bonded to phenylrings, may be contained one or more times in the definitions of thesubstituents of compounds of Formula I or of Formula X, these mayusually be contained one to three times. If one or more carbon atoms maybe replaced by heteroatoms such as oxygen, sulfur or nitrogen incompounds of the present invention, usually one to three carbon atomsmay be replaced by heteroatoms. Preferably one carbon atom may bereplaced by a heteroatom. If substituents may contain one or more doublebonds, cyclic substituents, depending on ring size, may usually contain1-4 double bonds and may preferably form aromatic systems. Aliphaticsubstituents may, for example, contain 1 to 3 double bonds, depending onchain length.

Preferably, compounds of Formula Ia may be produced wherein thesubstituents R¹ and R² each stand for hydrogen. Particularly preferably,compounds of the general formula Ib may be produced, in particular whenthe substituent R¹⁰¹ is hydrogen.

The substituent R³ may preferably stand for hydrogen, or, together withR⁴, may form an optionally bridged C₃-C₆-alkylene chain. Preferablythose compounds of Formula I wherein R⁴ is not hydrogen, but, forexample, lower alkyl, may be produced in isomerically pure manner. If R⁴has a meaning other than hydrogen, the ring closure reaction to formcompounds of Formula Xa in process step b) takes place with particularlyhigh selectivity, and the compounds of Formula Ia and of Formula Iobtained from the compounds of Formula Xa may be obtained with aparticularly low proportion of byproducts. If R³ and R⁴ together standfor an optionally bridged C₃-C₆-alkylene chain, the alkylene chain maypreferably contain 3 to 4 carbon atoms. If the alkylene chain isbridged, the bridging chain may preferably have 1 carbon atom, which maypreferably be substituted by di-lower alkyl. In particular, R³ and R⁴,together with the carbon atoms to which they are bonded, may form the7,7-dimethylbicyclo[3.1.1]heptane system.

If the substituent R⁸ is or contains optionally esterified carboxy, thecarboxyl group may be esterified with conventional,non-sterically-hindered alcohols, for example with cycloaliphatic orstraight-chain or branched aliphatic C₁-C₈-alcohols optionallycontaining one or more double bonds, which alcohols may optionally besubstituted one or more times by halogen or lower alkoxy, oralternatively with phenyl-lower alkyl alcohols optionally substitutedone or more times in the phenyl ring by lower alkyl, lower haloalkyl,lower alkoxy or lower haloalkoxy. If R⁸ is or contains carbonylaminooptionally substituted one or two times at the nitrogen, the amino groupcontained therein may for example be substituted once byC₃-C₈-cycloalkyl-lower alkanoyl or straight-chain or branched aliphaticC₁-C₈-alkanoyl, each of which may optionally be substituted one or moretimes by halogen or lower alkoxy, or the amino group may be substitutedonce by phenyl-lower alkanoyl optionally substituted one or more timesin the phenyl ring by lower alkyl, lower haloalkyl, lower alkoxy orlower haloalkoxy, or the amino group may for example also be substitutedone or two times by C₃-C₈-cycloalkyl-lower alkyl or straight-chain orbranched aliphatic C₁-C₈-alkyl, each of which optionally may besubstituted one or more times by halogen or lower alkoxy; phenyl-loweralkyl optionally substituted one or more times in the phenyl ring bylower alkyl, lower haloalkyl, lower alkoxy or lower haloalkoxy; or theamino group may for example be protected with a suitable aminoprotecting group. If R⁸ is or contains an optionally substitutedmonocyclic or bicyclic ring system with 3 to 10 ring carbon atoms, thismay for example stand for cyclopropyl, cyclopentyl, cyclohexyl, phenyl,p-bromophenyl or 3-indolyl.

Examples of compounds of Formula I, Ia, Ib and/or Ic according to theinvention which can be produced without difficulty using the processaccording to the invention have as substituents R⁸ or R⁸⁰¹ hydrogen,lower alkyl, phenyl, lower-alkyl phenyl or lower-alkyloxy lower alkyl,or for example also contain a fused aromatic bring formed from R⁸, orR⁸⁰¹, R⁵, R⁶ and R⁷. Likewise, compounds of Formula I, Ia, Ib and/or Icin which R⁸⁰¹ together with R⁹⁰¹ forms a C₃-C₄-alkylene chain can beproduced without difficulty.

Suitable protecting groups which can be used in the compounds given inthe context of the present invention are known, for example from McOmie,“Protective Groups in Organic Chemistry”, Plenum Press, or from Green,Wuts, “Protective Groups in Organic Synthesis”, Wiley IntersciencePublication.

The deprotonation of compounds of Formula II with suitable bases and thereaction of the deprotonated compounds of Formula II with organometallicreagents of Formula VII and then with the aminoaldehydes of Formula VIIto form the compounds of Formula IX in process step a) can be carriedout in a polar or weakly polar aprotic solvent which is inert under thereaction conditions, for example in cyclic or open-chained lower-alkylethers such as diethyl ether (=ether) or tetrahydrofuran (=THF), inlow-molecular polyethylene glycol ethers such as diethylene dimethylether (=diglyme) or in substituted benzenes such as toluene or xylene.Preferably, weakly polar solvents such as substituted benzenes, inparticular toluene, may be used. If toluene is used as solvent,particularly good yields of the products of Formula IX or of theproducts of Formula Xa obtained therefrom are obtained. Advantageously,the reaction can be performed as a one-pot reaction, by deprotonating apreferably isomerically pure 2-alkenyl sulfoximide of Formula II in asuitable solvent as named above at low temperature, for example between−100° C. and −50° C., preferably at −78° C., for about 5 to 30 minuteswith a suitable base, transmetalating the deprotonated form of thecompound of Formula II at slightly elevated temperature, for examplebetween −20° C. and 10° C., preferably at 0° C., with an organometallicreagent of Formula VII, and then, again at low temperature, for examplebetween −100° C. and −50° C., preferably at −78° C., reacting theresulting intermediate product with an N-protected aminoaldehyde ofFormula VII. Suitable bases for deprotonating compounds of Formula IIare preferably lithiated lower alkyl compounds such as n-butyllithium.Usually, the base may be used in a slight excess, for example in a molarratio of about 1:1.05 to about 1:1.20, relative to the quantity of thecompound of Formula II used. In organometallic reagents of Formula VII,X may stand for halogen, preferably for chlorine. Zirconium, forexample, but preferably titanium, may be used as the tetravalenttransition metal M². Suitable substituents R¹² are, for example,branched and unbranched lower alkyl groups, preferably isopropyl.Particularly preferably, chlorotris(isopropoxy)titanium may be used asthe compound of Formula VII. The organometallic reagent isadvantageously used in a slight excess, for example in a molar ratio ofabout 1.1:1 to 1.3:1, relative to the quantity of the compound ofFormula II which is used.

The compounds of Formula VIII represent protected chiral α- orβ-aminoaldehydes, and may preferably be used in isomerically pure form.Suitable protecting groups R¹³ which when cleaved produce a nucleophilicnitrogen atom in compounds of Formula VIII are preferably base-labileprotecting groups. Particularly preferably, thefluoren-9-yl-methyloxycarbonyl protecting group (=FMOC) may be used asgroup R¹³. The cleaving of the protecting group R¹³ and the ring closurereaction may preferably take place in a single reaction step, providedthat FMOC is used as protecting group.

In the starting compounds of Formula VIII, the substituent R⁸⁰¹ has themeaning given for R⁸, but if need be reactive groups contained in thesubstituent R⁸, for example hydroxy, amino, mercapto or carboxy, areeach blocked by known base-stable protecting groups, for exampleprotecting groups stable against non-nucleophilic or weakly nucleophilicbases such as pyridine, in order to avoid unwanted side-effects.Isomerically pure aminoaldehydes of Formula VIII are known, or can beproduced from known compounds in known manner. Thus, for example, thealdehydes of Formula VIII can be obtained by known mild oxidationprocesses from the primary alcohols corresponding to the aldehydes.Suitable mild oxidation processes are those processes which do not causeracemisation of the chiral centres in compounds of Formula VIII, forexample the oxidation with activated oxalyl chloride (=Swem oxidation)or alternatively oxidation with1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (=periodinane;Dess-Martin oxidation, see, e.g. J. C. Martin et al., JACS 113 (1991),7277-7287; D. B. Dess, J. C. Martin, Journal of Organic Chemistry 48(1983), 4155-4156). If the oxidation takes place in accordance with theDess-Martin method referred to above, an aminoaldehyde of Formula VIIIcan be produced according to a process mentioned in the aboveliterature, or a process analogous thereto. For example, a primaryalcohol suitable as precursor for an aldehyde of Formula VIII in adipolar-aprotic solvent, for example in a halogenated lower alkane suchas dichloromethane, may be reacted with a slight excess of thetriacetoxy periodinane, for example in a molar ratio of about 1.2:1 toabout 1.4:1, relative to the compound of Formula VIII which is used. Thereaction can be carried out at temperatures between −20° C. and roomtemperature, preferably at 0° C.

The primary alcohols corresponding to the aldehydes of Formula VIII areknown or can be produced from known precursor compounds by knownprocesses. For example, the primary alcohols may be produced by knownreduction processes, for example by reduction with complex alkali metalhydrides such as lithium aluminium hydride, from the corresponding freeaminocarboxylic acid precursor compounds. Preferably aminocarboxylicacids which are already present in isomerically pure, for exampleenantiomerically pure, form, such as the known, naturally occurring 20proteinogenic α-amino acids, are suitable. Likewise, commerciallyavailable unnatural isomerically pure α-amino acids obtainable, forexample, from the company ChiroTech, Cambridge (catalogue “TheChiroChem™ Collection, Series 1, FMOC unnatural amino acids formedicinal and combinatorial chemists”, SCRIP No. 2311/20.02.1998, page15), can be used. For the production of compounds of Formula I whereinn=1, the point of departure may expediently be isomerically pure β-aminoacids known per se, for example from Nohira et al, Bulletin of theChemical Society of Japan 43 (1970) 2230 ff. Furthermore, isomericallypure β-amino acids suitable for the invention can also be produced fromisomerically pure α-amino acids by homologisation, for examplehomologisation according to Amdt-Eistert in accordance with the methodsof D. Seebach et al., Helvetica Chimica Acta (=HCA) 79 (1996) 913-941;2043 ff. and Synlett (1997) 437 ff. α-chiral, β-amino acids wherein R⁵has a meaning other than hydrogen can be obtained in known manner, forexample by asymmetrical alkylation of chiral oxazolidinones withchloromethyl amides in accordance with the method of D. Seebach et al.,Synlett (1997) 437 ff., or alternatively in accordance with other knownmethods.

The desired protecting groups R¹³ can be introduced into compounds ofFormula VIII or the precursor compounds thereof mentioned above usingknown methods.

In process step a), two new stereogenic carbon atoms are produced in thevinyl sulfoximides of Formula IX by the reaction between a chiralaminoaldehyde of Formula VIII and the chiral intermediate productresulting from a 2-alkenyl sulfoximide of Formula II by deprotonationand transmetalation. These new stereogenic carbon atoms are the atomsC-3 and C-4 in compounds of Formula IX. The substituents R⁴ on C-4 andOM²(OR¹²)₃ on C-3 as a rule adopt an “anti” orientation to each otherwith high selectivity of at least 95% upon the formation of the vinylsulfoximides of Formula IX according to the process of the invention.The absolute configurations at the newly produced chiral centres C-3 andC-4 are then controlled during the reaction in each case by the absoluteconfiguration at the sulfur atom in compounds of Formula II in themanner of a regio- and diastereo-controlled reaction. If the sulfur atomin compounds of Formula II is in the R configuration, the prochiralcarbonyl group in the aldehydes of Formula VIII will be attacked fromthe Si side. If, on the other hand, the sulfur atom in compounds ofFormula II is in the S configuration, the prochiral carbonyl group inthe aldehydes of Formula VIII will be attacked from the Re side. Owingto the absolute configuration of the compounds of Formula IX which isestablished in this manner, the stereochemistry of the compounds ofFormulae Ia, lb and Ic is also established at the corresponding chiralcentres as a “cis” orientation. The absolute configuration at the chiralcarbon atom of an aminoaldehyde of Formula VIII scarcely has anyinfluence on the stereochemistry on the carbon atoms C-3 and C-4 of thecompounds of Formula IX.

The treatment of compounds of Formula IX with a reagent suitable forcleaving the protecting group R¹³ in process step b) in order to obtaincompounds of Formula Xa can be effected immediately following processstep a) in situ in known manner, without isolation of the compounds ofFormula IX being necessary. Accordingly, the reaction can be performedin solvents stated above and at temperatures given above between −100°C. and −50° C., preferably at −78° C. Base-labile protecting groups may,for example, be cleaved with known non-nucleophilic or weaklynucleophilic organic bases which are soluble in the reaction mixture. Ifthe FMOC group is used as amino protecting group R¹³, piperidine ispreferred as a base for the cleavage thereof. Usually the base is usedin a hyperstoichiometric quantity, for example in a molar ratio of about5:1 to about 15:1, preferably of about 10:1, relative to the quantity ofcompounds of Formula IX resulting from compounds of Formula II which isused. Once addition of the base has taken place, first of all thawing to0° C. and later to room temperature can be effected, and the reactionmixture can be worked up in conventional manner, in which caseoptionally resulting byproducts can be separated in known manner, forexample by crystallisation and/or chromatography.

Due to the cleaving of the amino protecting group R¹³ from compounds ofFormula IX, preferably due to the base-induced cleaving thereof, a ringclosure reaction to form compounds of Formula Xa is initiated. Inparticular for compounds of Formula IX in which R⁴ is not hydrogen, thecyclisation reaction takes place such that the sulfonimidoyl radical inthe 5-position of the resulting compound of Formula Xa preferentiallyadopts the “trans” position to the hydroxyl group in the 3-position ofthe resulting ring skeleton.

In resulting azacyclic compounds which contain a secondary ring nitrogenatom, this nitrogen atom can then be further reacted in known mannerwith a compound which contains a group suitable for reaction with asecondary amine. For example, a reaction of the nitrogen atom with knowncarboxylic acids to form peptide bonds can take place. Likewise, theabove nitrogen atom can also be alkylated in known manner, for exampleby reacting with an alkyl halide such as a phenyl-lower alkyl halide,for example benzyl chloride. Using these methods described above, or inanother known manner, the nitrogen atom may also be blocked with aconventional amino protecting group, preferably a base-stable protectinggroup. In particular, it is advantageous to block the ring nitrogen atomin compounds of Formula Xa with a base-stable protecting group ifcompounds of Formula Ib are to be produced. Suitable base-stableprotecting groups are preferably protecting groups which form acarbamate, in particular the tert. butyloxycarbonyl protecting group(=BOC).

Any protecting groups can if desired also be cleaved off again in knownmanner, optionally selectively, from compounds of Formula Xa. Forexample, it may in particular be advantageous to cleave off a silylprotecting group R¹¹ which may possibly still be present after processstep b) from compounds of Formula Xa before reaction with a reagentsuitable for reductive cleavage of the sulfonimidoyl-alkyl bond inprocess step ca) in known manner, provided that this cleavage of thesilyl protecting group has not taken place spontaneously in process stepb). An example of a silyl protecting group which is usuallyspontaneously cleaved off in process step b) without requiringadditional treatment is trimethylsilyl (=TMS).

Compounds of Formula Xa or compounds obtainable from compounds ofFormula Xa by cleaving off protecting groups are novel compounds havinguseful properties, and may, for example, serve as intermediate productsfor the production of compounds of Formula I.(2S,3R,4R,5R,S_(S))-2-benzyl-3-hydroxy-5-{N-[(S)1-hydroxy-3-methylbut-2-yl]-4-methylphenylsulfonimidoylmethyl}-4-methyl-1-(4-methylphenylsulfonyl)pyrrolidineis already known from the Internet publication at the address“www.iucr.ac.uk” by M. Bolte, Acta Crystallographica Section C,electronically published paper QA0019[=(IUCr) Acta C Paper QA0019].However, no process for the production of this compound is mentioned inthe publication cited.

The reductive cleavage of the sulfonimidoyl-alkyl bond in a resultingcompound of Formula Xa or in a compound obtained from a compound ofFormula Xa by the reactions at the ring nitrogen atom described above inprocess step ca) for the production of compounds of Formula Ib can beperformed in a polar or weakly polar solvent given above for thereaction of compounds of Formula II with compounds of Formula VII or inmixtures of these solvents. Preferably THF may be used. The reaction canbe performed at temperatures between −20° C. and room temperature,preferably at 0° C. Suitable reagents for cleaving thesulfonimidoyl-alkyl bond are, for example, reducing agents such as Raneynickel, lithium naphthalenide or samarium (II) iodide. Preferablysamarium (II) iodide may be used.

If the desulfurisation is performed with samarium (II) iodide, this canbe produced in known manner in situ from samarium and diiodomethane.Usually the samarium (II) iodide is then used in a hyperstoichiometricquantity, for example in a molar ratio of about 3:1 to about 7:1,relative to the compound of Formula Xa used. To perform the reaction, aproton source, such as a protic compound soluble in the solvent used, isadded in a suitable quantity to the reaction mixture consisting ofcompound of Formula Xa and samarium diiodide. A lower alcohol such asmethanol, for example, may be used as proton source. Preferablyanhydrous methanol is used. A suitable quantity of the proton sourcemay, for example, be between 2 and 5 equivalents, relative to oneequivalent of the quantity of sulfur contained in a compound of FormulaXa. Compounds of Formula Xa in which a secondary ring nitrogen atom isblocked by a carbamate protecting group, preferably the BOC protectinggroup, can be used particularly advantageously in this case.

The cleavage of the sulfonimidoyl-alkyl bond under the conditions of abase-induced reductive elimination in a resulting compound of Formula Xawherein R¹⁰¹ is not hydrogen, or in a compound obtained from a compoundof Formula Xa by the reactions at the ring nitrogen atom described abovein process step ca) for the production of compounds of Formula Ic can becarried out in a polar or weakly polar solvent given above for thereaction of compounds of Formula II with compounds of Formula VII, oralternatively in a partially halogenated lower-alkyl solvent such asdichloromethane. Preferably dichloromethane may be used. Suitable basesfor cleaving the sulfonimidoyl-alkyl bond by β-elimination arenon-nucleophilic organic bases such as bicyclic amidines, for example1,5-diazabicyclo[4.3.0]-5-nonene (=DBN) or1,8-diazabicyclo[5.4.0]-7-undecene (=DBU). Preferably DBU may be used.Expediently, the reaction is performed such that the sulfonimidoyl groupof a compound of Formula Xa given above is electrophilically activatedin known manner. To this end, the compound of Formula Xa may be reactedat temperatures between −25° C. and −15° C. with a compound suitable forforming a good leaving group from the sulfonyl group, or with alower-alkyl oxonium tetrafluoroborate such as trimethyloxoniumtetrafluoroborate, known as “Meerwein salt”. Reagents which are capableof forming a good leaving group by attacking the sulfonyl group are, forexample, esters or halides of sulfonic acids such as methanesulfonicacid chloride, trifluoromethanesulfonic acid chloride,trifluoro-methanesulfonic acid methyl ester (=methyl triflate) ortrifluoro-methanesulfonic acid trimethylsilyl ester (=TMS triflate).Preferably methyl triflate may be used. Usually, the resulting reactionmixture is allowed to thaw to room temperature once reaction has takenplace, and then the above-mentioned base is added.

In the resulting compounds of Formula Ia, the relative orientation ofthe sulfonimidoyl substituent in the 5-position and of the hydroxylgroup in the 3-position resulting in process step b) by ring closure toform compounds of Formula Xa is established as a “trans” orientation toeach other. Compounds of Formula I wherein the substituent YH in the3-position may be hydroxy or amino and/or wherein the substituents YH inthe 3-position and R¹—CHR²— in the 5-position may also be in the “cis”orientation to each other may be obtained if desired from compounds ofFormula Ia by a nucleophilic substitution reaction at the ring carbonatom in the 3-position performed one or more times and taking place withinversion; Such nucleophilic substitution reactions are known per se andmay be performed, for example, under the conditions of a Mitsunobureaction (see e.g. Mitsunobu, Synthesis 1 (1981) 1-28).

If, for example, compounds of Formula I wherein YH stands for hydroxyand wherein the substituents OH in the 3-position and R¹—CHR²— in the5-position are in a “cis” orientation to each other are desired,expediently a Mitsunobu reaction can be performed in that a solution ofa compound of Formula Ia, wherein if necessary any additional hydroxylgroups present are blocked by protecting groups, and oftriphenylphosphine in an organic solvent which is inert under thereaction conditions, such as a cyclic or open-chained lower-alkyl ether,for example diethyl ether or THF, are added to a receiving solutionconsisting of a solution of diethyl azodicarboxylate (=DEAD) and anacid, for example phosphoric acid or a carboxylic acid such as benzoicacid. The reaction can preferably be performed at room temperature. Theester of a desired compound of Formula I obtained in this manner may ifdesired then be cleaved in known manner, in order to obtain the freehydroxyl group in the 3-position.

If, for example, compounds of Formula I in which Y stands for NH andwherein the substituents amino in the 3-position and R¹—CHR²— in the5-position are in a “cis” orientation to each other are desired,expediently a Mitsunobu reaction can be performed such that a solutionof DEAD in an inert solvent named above is added to a receiving solutionconsisting of a solution of triphenylphosphine, a compound of FormulaIa, wherein if necessary additional hydroxyl groups present are blockedby protecting groups, and a reagent suitable for nucleophilicsubstitution of a hydroxyl group by an amino group in aliphaticradicals, such as phthalimide. The resulting intermediate product, forexample an N-substituted phthalimide, can then be treated in a proticsolvent such as a lower alkanol, for example ethanol, with a reagentsuitable for releasing the resulting amine of Formula 1, such ashydrazine.

If, for example, compounds of Formula I are desired wherein Y stands forNH and wherein the substituents YH in the 3-position and R¹—CHR²— in the5-position are in a “trans” orientation to each other, in a compound ofFormula Ia as given above first of all an inversion of the ring carbonatom in the 3-position as described above can be performed, obtainingthe hydroxy substituent, and a substitution of the hydroxyl group by anamino group, as described above, with renewed inversion of the ringcarbon atom in the 3-position can then be performed on this intermediateproduct of Formula 1.

The resulting compounds of Formula I may be isolated from the reactionmixture in known manner. Any protecting groups may if desired be cleavedoff again in known manner, optionally selectively, and the group YH mayif desired be blocked with known protecting groups. The possiblyreleased NH group in the 1-position of the cyclic parent structure mayif desired be reacted with the above-mentioned reagents capable ofN-alkylation or of amide formation, or be blocked with an aminoprotecting group. If desired, compounds of Formula I which contain basicamino groups may be converted into acid addition salts in known manner.Suitable acids for this purpose are, for example, mineral acids such ashydrochloric acid or sulfuric acid, or organic acids such as sulfonicacids, for example methylsulfonic acid or p-toluenesulfonic acid, orcarboxylic acids such as acetic acid, trifluoroacetic acid, tartaricacid or citric acid.

The compounds of the general formulae Ia, lb and Ic are novel compounds,and represent valuable starting materials, for example for theproduction of chiral catalysts for asymmetric synthesis, for theproduction of biologically active alkaloids or porphyrins and for theproduction of pharmacologically interesting compounds.

The starting compounds of Formula II can be produced in known manner.

For example, compounds of the general formula IIa

wherein R¹⁰¹, R⁴, R¹⁰, R¹¹⁰¹ and Ar have the above meanings, may beproduced by reacting a stereoisomer of a compound of the general formulaIII,

wherein Ar and R¹⁰ have the above meanings, with a compound of thegeneral formula IV,

wherein R¹⁰¹ and R⁴ have the above meanings and M¹ stands for amonovalent group containing an alkali metal or an alkaline earth metaland a halogen atom, and blocking a hydroxyl group which is released ifnecessary upon this reaction with a silyl protecting group R¹¹⁰¹.

The reaction of a stereoisomer of cyclic sulfonimidates of Formula IIIwith a metalated alkene of Formula IV to form an isomerically pure2-alkenyl sulfoximide of Formula II can be performed in a polar orweakly polar aprotic solvent given above for the reaction of compoundsof Formula II with compounds of Formula VII. Preferably, THF can beused. The reaction can be performed by mixing the reactants at atemperature of −100° C. to −50° C., preferably at −78° C., in a solventgiven above and allowing the resulting reaction mixture to react for ashort time, e.g. 2 to 10 minutes, at the given temperature and thenwarming it to a higher temperature below room temperature, for exampleto −20° C. to 0° C. If necessary, stirring can be continued for a whileat −20° C. to 0° C. to complete the reaction. It is advantageous to usethe compound of Formula IV in hyperstoichiometric quantities. Forexample, 1.5 to 2.5 mole of a compound of Formula IV may be reacted withone mole of a compound of Formula III.

In the cyclic sulfonimidates of Formula II, Ar may preferably stand for4-methylphenyl (=p-tolyl). R¹⁰ may be in particular methyl, isopropyl,isobutyl or phenyl, and preferably stands for isopropyl.

In order to achieve desired stereochemically controlled production ofthe compounds of Formula I, the sulfonimidates of Formula III should beused in isomerically pure form. “Isomerically pure” in the context ofthe present invention should be understood fundamentally to mean anexcess of isomer (=excess of enantiomer, ee, or excess ofdiastereoisomer, de) of a pure isomer of at least 95%. In the formulaegiven in the context of the present invention, the “*”, (asterisk) signin each case indicates a chiral centre which is usually produced inisomerically pure manner or originates from educts usually used inisomerically pure manner. If non-isomerically pure, for example racemic,starting compounds are used to produce compounds of Formula I, of courseisomer mixtures of compounds of Formula I can also be obtained using theproduction process according to the invention. If sulfonimidates ofFormula III are used in which the chiral sulfur atom and the chiralcarbon atom bearing the substituent R¹⁰ have different absoluteconfigurations (i.e. if, for example, the sulfur atom is in the Rconfiguration and the carbon atom bearing the substituent R¹⁰ is in theS configuration), particularly good results are achieved in terms of thestereochemical purity of the products of Formula I. Particularlypreferably,(R_(S))-4(R)-isopropyl-2-p-tolyl-4,5-dihydro[1.2λ⁶.3]oxathiazol-2-oxideand(S_(S))4(R)-isopropyl-2-p-tolyl-4,5-dihydro[1.2λ⁶.3]oxathiazol-2-oxidemay be used as compounds of Formula III. The expressions R_(S) and S_(S)each designate the absolute configuration at the chiral sulfur atom.Sulfonimidates of Formula III are known, for example, from Reggelin etal, Tetrahedron Letters (=TL) 33 (1992) 6959-6962 or from Reggelin etal, TL 36 (1995) 5885-5886, and may be produced in isometrically pureform according to the processes referred to therein or processesanalogous thereto.

In the metalated compounds of Formula IV, the monovalent group M¹ may bean alkali metal, preferably lithium, or a group containing an alkalineearth metal and additionally a halogen atom. Magnesium is preferred asalkaline earth metal. Chlorine, bromine or iodine can be used ashalogen. In particular, known lithiated alkenyl compounds or knownmagnesium-organic alkenyl compounds, such as alkenyl Grignard reagents,may be used as metalated compounds of Formula IV.

Usually, a hydroxyl group which is released upon the reaction ofcompounds of Formula III with compounds of Formula IV to form compoundsof Formula IIa is blocked with a suitable silyl protecting group R¹¹⁰¹in order to prevent undesirable subsequent reactions. Preferablytrimethylsilyl (=TMS) can be used as the silyl protecting group R¹⁰¹ incompounds of Formula IIa.

Compounds of the general Formula IIb,

wherein R¹⁰¹, R¹⁰, R¹¹⁰¹ and Ar have the above meanings and a ismethylene or a C₂-C₅-alkylene chain which may be bridged byC₁-C₂-alkylene which is optionally substituted one or two times by loweralkyl, may be produced, for example, by deprotonating a stereoisomer ofa compound of the general formula V,

wherein R¹⁰, R¹¹⁰¹ and Ar have the above meanings, with a base suitablefor the deprotonation thereof, reacting the deprotonated compound ofFormula V with a compound of the general formula VI,

wherein a has the above meaning, and treating the resulting intermediateproduct in succession with a reagent which permits cleavage of theoxygen atom derived from the carbonyl group of the compound of FormulaVI and with a base given above suitable for the deprotonation of acompound of Formula V.

The reaction sequence for producing cycloalkenyl methyl sulfoximidecompounds of Formula IIb by reacting compounds of Formula V withcompounds of Formula VI may expediently be performed as a one-potreaction sequence. The reaction of a stereoisomer of a methylsulfoximide of Formula V with a base suitable for the deprotonationthereof and the following reaction steps: reaction of the deprotonatedcompound of Formula V with a compound of Formula VI, treatment of theresulting intermediate product with a reagent which permits the cleavageof the oxygen atom derived from the carbonyl group of the compound ofFormula VI and renewed treatment with a base as stated above, are knownper se and may be performed in accordance with a process mentioned inReggelin et al, JACS 118 (1996) 4765-4777 or one analogous thereto. Thegroup Ar and the substituent R¹⁰ in compounds of Formula V may have thepreferred meanings given above for compounds of Formula III. Preferablytert. butyl dimethylsilyl (=TBS) may be used as silyl protecting groupR¹¹⁰¹ in compounds of Formula V. Analogously to the preferredstereochemical conditions given above for compounds of Formula III,preferably [S_(S),N(1S)]-N-[1-[[tert.butyldimethylsilyl)oxy]methyl]-2-methylpropyl]-S-methyl-S-(4-methylphenyl)sulfoximide and [R_(S),N(1R)]-N-[1-[[tert.butyidimethylsilyl)oxy]methyl]-2-methylpropyl]-S-methyl-S-(4-methylphenyl)sulfoximide may be used as compounds of Formula V. Lithiated lower alkylcompounds such as n-butyllithium are, for example, suitable as bases fordeprotonation of compounds of Formula V. The compounds named above forthe formation of a good leaving group by attack on the oxygen atom ofthe sulfonyl group in compounds of Formula Xa are suitable as reagentswhich permit the cleavage of oxygen atoms derived from the carbonylgroup of compounds of Formula VI. Preferably, TMS triflate can be used.

The alicyclic ketones of Formula VI are known. For example,cyclopentanone, cyclohexanone or nopinone may be used as compounds ofFormula VI. If bridged cyclic ketones are used as compounds of FormulaVI, it is advantageous if the bridging alkylene chain is bonded to atleast one of the two carbon atoms in the α-position to the carbonylgroup. In this manner, the reaction products are always formed withcontrolled regioselectivity.

Another possible way of obtaining compounds of Formula IIb is thereaction of a compound of the general formula XII,

wherein a and Ph have the above meanings, each with a reagent suitablefor the lithiating deselenation thereof and the subsequent reaction ofthe deselenated lithiated intermediate product produced in each casewith a stereoisomer of a compound of Formula III.

The selenated compounds of Formula XII can be obtained in known mannerfrom the corresponding allyl alcohols by halogenation and subsequentreducing selenation. For example, the compounds of Formulae XII may beobtained according to the process mentioned by Reggelin et al in JACS118 (1996) 4765-4777 or to processes analogous thereto. Myrtenol may bementioned as an example of an allyl alcohol which is suitable for theproduction of selenated compounds of Formula XII.

The production of compounds of Formula IIb by reaction of compounds ofFormula XII with compounds of Formula III can be performed in knownmanner, for example in accordance with the method for the production ofcycloalkenyl sulfoximide compounds referred to in the publication byReggelin et al, JACS 118 (1996) 4765-4777, to which reference isexpressly made hereby.

In one variant of the invention, compounds of Formula II wherein R¹⁰¹has a meaning other than hydrogen can be produced by simplydeprotonating compounds of Formula II wherein R¹⁰¹ stands for hydrogenwith a base suitable for this purpose, and then alkylating them byreaction with a compound of the general formula XI,R¹⁰³—Z  XIwherein R¹⁰³ has the meaning given for R¹⁰¹ with the exception ofhydrogen and Z stands for a cleavable leaving group. Suitable examplesof bases for a deprotonation as referred to above are, for example,lithiated lower alkyl compounds such as n-butyllithium. Halogen,preferably bromine or chlorine, may for example be used as cleavableleaving group Z in compounds of Formula XI. The reaction can beperformed under conventional reaction conditions for this type ofreaction.

The following examples are intended to explain the invention further,without restricting its scope.

The numbering of the ring atoms in the example compounds, in particularof the chiral carbon atoms, relates to the numbering of the ring atomsgiven in general formula 1.

EXAMPLE 1

(+)-(2S,3S,4S,5S)-2-isobutyl-3-hydroxy-4,5-dimethyl-N-tert.butoxycarbonyl-pyrrolidine

-   A) 6.0 g FMOC-amino-protected S-2-amino-4-methylpentanol (obtained    by lithium aluminium hydride reduction of leucine) was suspended in    100 ml dichloromethane under a nitrogen atmosphere and with water    excluded and cooled to 0° C. To this receiving solution was added    10.0 g 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one    (=periodinane) in one portion as a solid, and the resulting reaction    mixture was stirred for two hours at room temperature. Then the    reaction mixture was poured onto a solution of 130 ml of a 10%    strength aqueous sodium thiosulfate solution and 360 ml of a    saturated aqueous sodium hydrogen carbonate solution covered with    100 ml ether. The aqueous phase was extracted once with 100 ml    ether, the combined organic phases were washed with a saturated    aqueous sodium chloride solution and were dried over sodium sulfate.    The solvent was evaporated under reduced pressure and the crude    FMOC-protected S-2-amino-4-methyl valeraldehyde obtained in this    manner was used for the following reaction without further    purification.    -   To determine the optical purity, a portion of the resulting        aldehyde was isolated by crystallisation from ether/hexane. The        excess of enantiomer was determined by NMR spectroscopy with        addition of the chiral shift reagent        tris-[3-(heptafluoropropyl-hydroxymethylene)-d-camphorato]-praseodymium (III)        [=Pr(hfc)₃]. The excess of enantiomer (ee) was determined as 95%        by integration of the baseline-separated signals of the aldehyde        protons.-   B) 1.82 g magnesium chippings were covered with approximately 10 ml    diethyl ether and activated by addition of 500 mg freshly distilled    crotyl bromide. A solution of 10.0 g crotyl bromide    (=cis/trans-1-bromo-2-butene) in 100 ml diethyl ether was added    slowly dropwise to this receiving solution at 0° C. with protection    by argon and with moisture excluded. The resulting mixture was    heated to boiling for 30 minutes once addition had taken place. The    resulting ethereal solution of crotyl magnesium bromide was    separated from non-reacted magnesium and was reacted further    directly in solution without further working-up.    -   To determine the content of the Grignard solution produced        above, a solution of 180 mg (−)-menthol and a spatula-tip of        phenanthroline in 3.0 ml THF was cooled to 0° C. By adding the        Grignard solution to this receiving solution, titration was        performed until the colour changed to red, and the quantity of        Grignard solution required for the following reaction was        determined by differential weighing. The content of the Grignard        solution in mmol/g is yielded from the quotient of the quantity        of menthol weighed in in mmol and the weight in g of the        Grignard solution required for titration until the colour        change.-   C) 46 g of the solution of crotyl magnesium bromide dissolved in 100    ml diethyl ether obtained above was added dropwise to a solution of    2.3 g    (+)—(R_(S))-4(R)-isopropyl-2-p-tolyl-4,5-dihydro[1.2λ⁶.3]oxathiazol-2-oxide    in 40 ml THF cooled to −40° C., with protection by argon and with    moisture excluded. Once addition had been completed, stirring was    carried out for five minutes at the given temperature before the    reaction mixture was allowed to warm to 0° C. Stirring was continued    at this temperature for a further 45 minutes, and then 50 ml of a    saturated aqueous ammonium chloride solution was added. The organic    phase was separated, the aqueous phase was extracted twice with    ether and the combined organic phases were dried over sodium    sulfate. Then the solvent was evaporated under reduced pressure and    the residue was chromatographed over silica gel (mobile solvent:    initially ethyl acetate/n-hexane 1:3 v/v, the composition of which    was continuously changed up to 3:1). 1.4 g    (R_(S),1R)-N-[1-(hydroxymethyl)-2-methyl-propyl]-S-(2-butenyl)-p-toluenesulfoximide    was obtained as a colourless oil, IR (film)=3440, 1220, 1115 cm⁻¹,    optical rotation [α]_(D) ²⁰⁼⁺3.3° (c=0.5 in dichloromethane).-   D) 0.6 ml chlorotrimethylsilane was added dropwise to a solution of    1.4 g of the sulfoximide obtained above and 0.7 ml ethyl    dimethylamine in 13 ml dichloromethane which had been cooled to 0°    C., with protection by argon and with moisture excluded. Once    addition had been completed, stirring was continued for 15 minutes    at 0° C. Then the solution was allowed to thaw to room temperature    and once complete reaction had taken place the reaction mixture was    poured onto a mixture of 25 ml ether and 25 g ice. The aqueous phase    was extracted three times with 10 ml ether each time, the organic    phases were combined and dried over magnesium sulfate. The solvent    was evaporated under reduced pressure, and the remaining residue was    purified by chromatography on silica gel (mobile solvent:    ether/n-hexane 1:1 v/v). 1.75 g    (+)(R_(S),1R)-N-[1-(trimethylsilyloxy-methylpropyl)-2-methyl]-S-(2-butenyl)-p-toluenesulfoximide    was obtained as a colourless oil, IR (film)=1240, 1080, 840 cm⁻¹,    optical rotation [α]_(D) ²⁰ =+15.5° (c=1.0 in dichloromethane).-   E) A solution of 1.47 g of the TMS-protected 2-alkenyl sulfoximide    obtained above in 8 ml toluene was cooled to −78° C. and 2.75 ml of    a 1.6-molar solution of n-butyllithium in n-hexane was added thereto    with protection by argon and with moisture excluded. The reaction    mixture was stirred for 15 minutes at the temperature given, and    then 4.8 ml of a 1-molar solution of chlorotris(isopropoxy)titanium    in n-hexane was added thereto. Stirring was continued for another 5    minutes at −78° C., the mixture was thawed to 0° C. and then stirred    for another 30 minutes at 0° C. Then the reaction mixture was cooled    again to −78° C. A solution of 2.8 g of the aminoaldehyde obtained    above under A) in 8 ml THF was added to this receiving solution.    Stirring was continued for 60 minutes at −78° C., 4 ml piperidine    was added and the mixture was warmed to 0° C. After 10 hours, the    reaction mixture was poured onto 120 ml of a thoroughly stirred,    saturated ammonium carbonate solution covered with 12 ml ethyl    acetate (=EA). This mixture was stirred for 30 minutes and then the    phases were separated. The organic phase was washed with 40 ml of a    saturated ammonium chloride solution and the combined aqueous phases    were extracted three times with EA. The combined organic phases were    dried over sodium sulfate and the solvent was evaporated under    reduced pressure. The remaining residue was taken up with a    suspension of 0.6 g potassium carbonate in 10 ml methanol and was    stirred for 60 minutes. Then non-dissolved potassium carbonate was    filtered out and the filtrate was cooled to 4° C. Precipitated solid    was filtered out, washing was effected with a little methanol which    was at a temperature of 4° C. and the filtrate was evaporated under    reduced pressure. The resulting residue was taken up in 5 ml toluene    and filtered over silica gel (mobile solvent: initially ether/hexane    1:3 v/v then EA). The polar, pyrrolidine-containing fraction was    reduced and taken up in 4 ml dioxan. 1.0 g di-tert. butyldicarbonate    [=(BOC)₂O] and a solution of 0.7 g sodium hydrogen carbonate in 8 ml    water were added to this receiving solution. The mixture was stirred    for 10 hours, the solvent was evaporated under reduced pressure and    the remaining residue was distributed between 5 ml water and 10 ml    ether. The aqueous phase was extracted three times with ether and    the combined organic phases were dried over sodium sulfate. After    renewed evaporation of the solvent under reduced pressure, the    resulting residue was purified by chromatography on silica gel    (mobile solvent: ether/hexane 3:1 v/v). 1.0 g    (R_(S),1′R,2S,3S,4S,5R)-N′-[(1-hydroxymethyl)-2-(methylpropyl)]-S-4-hydroxy-3-methyl-2-(4-methylphenylsulfonimidoylmethyl)-5-isobutyl-N-tert.    butoxycarbonyl-pyrrolidine was obtained as a colourless foam,    optical rotation [α]_(D) ²⁰=−4° (c=0.1 in dichloromethane), IR    (film)=3419, 1674, 1256, 1097 cm⁻¹.-   F) A total of 2.4 g diiodomethane was added dropwise to a suspension    of 1.67 g samarium in 40 ml THF which had been cooled to 0° C. Once    addition had taken place, the mixture was stirred for 15 minutes at    0° C. before the reaction mixture was thawed to room temperature.    Stirring was continued for another 60 minutes at room temperature,    and then a solution of 1.0 g of the 2-sulfonimidoylmethyl compound    obtained above in a mixture of 1.2 ml methanol and 2.5 ml THF was    added. The reaction mixture was stirred for 4 hours and then 110 ml    saturated aqueous ammonium chloride solution was added thereto.    After the first phase separation, 0.5 N aqueous hydrochloric acid    solution was added dropwise to the aqueous phase until the phase    cleared. The aqueous phase was extracted three times with ether. The    combined organic phases were dried over sodium sulfate and the    solvent was evaporated under reduced pressure. Chromatography of the    remaining residue on silica gel (mobile solvent: ether/n-hexane 3:1    v/v) yielded 0.5 g of the title compound as a colourless solid,    melting point 97° C., optical rotation [α]_(D) ²⁰=+66° (c=1.0 in    dichloromethane).

EXAMPLE 2

(+)-(2S,3S,4S,5R)-3-hydroxy-5-methyl-2-phenyl-(1-aza-N-tert.butoxycarbonyl)-bicyclo[3.3.0]octane

-   A) 16.6 ml of a 1,6-molar solution of methyllithium in hexane was    added dropwise to a solution of 3.98 g    (+)-(R_(S))-4R-isopropyl-2-p-tolyl-4,5-dihydro[1.2λ⁶.3]oxathiazol-2-oxide    in 40 ml THF cooled to −78° C., with protection by argon and with    moisture excluded. Once addition had been completed, stirring was    continued for five minutes at the given temperature before the    reaction mixture was allowed to warm to 0° C. Stirring was continued    at this temperature for a further 45 minutes, and then 160 ml    ammonium chloride was added. Once the organic phase had been    separated, the aqueous phase was extracted twice with 20 ml ether    and the combined organic phases were dried over sodium sulfate. Then    the solvent was evaporated under reduced pressure. The remaining    residue was dissolved in 80 ml dichloromethane at room temperature,    and 3.8 g tert. butyldimethylsilyl chloride, 0.6 g    N,N-dimethylaminopyridine and 2.4 g ethyldimethylamine were added    thereto and the mixture was stirred for 18 hours. Then the mixture    was poured on to 40 ml ice water, the organic phase was separated    and the aqueous phase was extracted three times with 20 ml    dichloromethane each time. After drying the combined organic phases    over sodium sulfate, the solvent was evaporated under reduced    pressure. Purification of the residue over silica gel (mobile    solvent: ether/n-hexane 1:1 v/v) yielded 6.0 g    (−)-R_(S)-N(1R)-N-[1-((tert.    butyidimethylsilyl)oxy)-methyl-2-methylpropyl]-S-methyl-S-(4-methylphenyl)sulfoximide    as a colourless oil, optical rotation [α]D_(D) ²⁰=43.2° (c=0.8 in    dichloromethane); IR (film)=1230, 1130 cm⁻¹.-   B) 12.45 ml of a 1.6-molar solution of n-butyllithium in n-hexane    was added dropwise to a solution of 6.5 g of the methylsulfoximide    obtained above in 45 ml toluene, which solution had been cooled to    −78° C., with protection by argon and with moisture excluded.    Stirring was carried out for 15 minutes at the temperature given and    then 2.2 g cyclopentanone was added undiluted thereto in drops.    After 10 minutes, the reaction mixture was warmed to room    temperature. Stirring was continued for a further 30 minutes at this    temperature before the batch was cooled to −78° C. and 9.2 g    trimethylsilyltrifluoro-methyl sulfonate was added thereto in drops.    After five minutes, the mixture was warmed to room temperature and    was stirred for a further three hours. Once it had been cooled again    to −78° C., 24.9 ml of a 1.6-molar solution of n-butyllithium in    n-hexane was added dropwise thereto. After three minutes' stirring    at the given temperature, the mixture was allowed to thaw to room    temperature and stirring was continued for another 18 hours. The    reaction mixture was poured on to 160 ml of a saturated aqueous    ammonium chloride solution, the mixture was extracted twice with    ethyl acetate and the combined organic phases were dried over sodium    sulfate. The solvent was evaporated under reduced pressure and the    remaining residue was purified over silica gel (mobile solvent:    ether/n-hexane 1:6 v/v). 5.5 g (−)-R_(S)-N(1R)-N-[1-((tert.    butyldimethylsilyl)oxy)methyl-2-methylpropyl]-S-cyclopent-1-en-1-ylmethyl)-S-(4-methylphenyl)sulfoximide    was obtained as a colourless oil, optical rotation [α]_(D) ²⁰=−2.5°    (c=1.6 in dichloromethane), IR (film)=1240, 1120 cm⁻¹.-   C) In the manner described above under 1E), a solution of 2.95 g of    the cyclopentenyl sulfoximide obtained above in 21 ml toluene was    reacted with 4.8 ml of a 1.6-molar solution of n-butyllithium in    n-hexane, 8.3 ml of a 1-molar solution of    chlorotris(isopropoxy)titanium in n-hexane, a solution of 5.0 g    FMOC-protected S-α-aminophenylethanal in 40 ml THF and 7 ml    piperidine. Chromatography on silica gel (mobile solvent:    ether/n-hexane=1:3 v/v) yielded 3.9 g (2S,3S,4S,5R)R_(S)-N(1    R)-N-[1-((tert.    butyidimethylsilyl)oxy)methyl-2-methylpropyl]-3-hydroxy-2-phenyl-5-(4-methylphenyl)sulfonimidoylmethyl-2-azabicyclo[3.3.0]octane.    Optical rotation [α]_(D) ²⁰+2.8° (c=0.6 in dichloromethane); IR    (film)=3443, 1251, 1103, 835 cm⁻¹.-   D) 0.45 g sodium hydrogen carbonate and 3.0 g di-tert. butyl    dicarbonate were added to a solution of 3.9 g of the bicyclic    compound obtained above in 20 ml dichloromethane and 40 ml water,    and the mixture was stirred for 12 hours. Once the solvent had been    evaporated under reduced pressure, the resulting residue was    distributed between 5 ml water and 10 ml ether. The organic phase    was separated, and the aqueous phase was extracted twice with ether.    Drying of the combined organic phases over sodium sulfate,    evaporation of the solvent under reduced pressure and chromatography    of the remaining residue on silica gel (mobile solvent:    ether/n-hexane=1:1 v/v) yielded 4.39 g    (−)-(2S,3S,4S,5S)-(-R_(S)-N(1R)N-[1-((tert.    butyldimethylsilyl)oxy)methyl-2-methylpropyl]-3-hydroxy-2-phenyl-5-(4-methylphenylsulfonimidoylmethyl-2-aza-(N-tert.    butoxycarbonyl)-bicyclo[3.3.0]octane, optical rotation [α]_(D)    ²⁰=−6.2° (c=0.9 in dichloromethane); IR (film)=3473, 1682, 1253, 837    cm⁻¹.-   E) 0.25 g tetrabutylammonium fluoride was added to a solution of    0.42 g of the bicyclic compound protected at the nitrogen obtained    above in 6 ml THF, which solution had been cooled to 0° C., the    mixture was warmed to room temperature after 15 minutes and then    stirred for another 12 hours. The reaction mixture was poured on to    10 ml water which was covered with 5 ml ether. Once the organic    phase had been separated, the aqueous phase was extracted three    times with ether, the combined organic phases were dried over sodium    sulfate and the solvent was evaporated under reduced pressure.    Chromatography on silica gel (mobile solvent: ethyl    acetate/n-hexane=1:1 v/v) yielded 0.35 g    (−)-(2S,3S,4S,5S)-R_(S)-N(1R)-N-[1-(hydroxymethyl)-2-methylpropyl]-3-hydroxy-2-phenyl-5-(4-methylphenylsulfonimidoylmethyl-2-aza-(N-tert.    butoxycarbonyl)-bicyclo[3.3.0]octane. [α]_(D) ²⁰=−14.1 (c=2.7 in    dichloromethane); IR (film)=3473, 1681, 1252 cm⁻¹.-   F) A total of 0.84 g diiodomethane was added dropwise to a    suspension of 0.56 g samarium in 13 ml THF which had been cooled to    0° C. Once addition had taken place, the mixture was stirred for 15    minutes at the given temperature before the reaction mixture was    thawed to room temperature. Stirring was continued for another 60    minutes, and then a solution of 0.28 g of the N-BOC-5-sulfonimidoyl    compound obtained above in a mixture of 1 ml methanol and 2 ml THF    was added. The reaction mixture was stirred for four hours and then    poured on to 110 ml of a saturated ammonium chloride solution. Once    the organic phase had been separated, 0.5 N hydrochloric acid    solution was added to the aqueous phase until the suspension had    cleared. The clear aqueous phase was extracted twice with ether, the    combined organic phases were dried over sodium sulfate and the    solvent was evaporated under reduced pressure. Chromatography of the    remaining residue on silica gel (mobile solvent: ether/n-hexane=1:4    v/v) yielded 0.11 g of the title compound as a colourless solid    body, melting point 176.8° C., [α]_(D) ^(°)=+50.7° (c=0.56 in    dichloromethane); IR (film)=3439, 1661 cm⁻¹.

EXAMPLE 3

(+)-(2S,3R,4R,5S)-3-hydroxy-5-methyl-2-phenyl-1-aza-(N-tert.butoxycarbonyl)-bicyclo[3.3.0]octane

-   A) 6.3 g    (−)-S_(S)-4R-isopropyl-2-p-tolyl-4,5-dihydro[1.2λ⁶.3]oxathiazol-2-oxide    was reacted with 6.03 g tert. butyldimethylsilyl chloride    corresponding to the manner described in Example 2A). 8.7 g    (+)-S_(S)-N(1R)-N-[1-((tert.    butyidimethylsilyl)oxy)-methyl-2-methylpropyl]-S-methyl-S-(4-methyl-phenyl)sulfoximide    was obtained as a colourless oil, optical rotation [α]_(D) ²⁰=+89.9°    (c=1.0 in dichloromethane), IR (film): 1251, 1134 cm⁻¹.-   B) In the manner described above under 2B), a solution of 8.04 g of    the methyl sulfoximide obtained above in 65 ml THF was reacted with    16.3 ml of a 1.6-molar solution of n-butyllithium in n-hexane, 3.1    ml cyclopentanone, 9.83 ml trimethylsilyltrifluoromethane sulfonate    and a further 27.19 ml of a 1.6-molar solution of n-butyllithium in    n-hexane. Chromatography on silica gel (mobile solvent:    ether/n-hexane=1:6 v/v) yielded 7.057 g (+)S_(S)-N((1R)-N-[1-((tert.    butyidimethylsilyl)oxy)methyl-2-methylpropyl]-S-cyclopent-1-en-1-ylmethyl)-S-(4-methylphenyl)-sulfoximide    as a colourless oil, optical rotation [α]_(D) ²⁰=+54.7° (c=1.35 in    dichloromethane), IR=1251, 1131 cm¹.-   C) In the manner described above under 1E), a solution of 3.17 g of    the cyclopentenyl sulfoximide obtained above in 22 ml toluene was    reacted with 5.6 ml of a 1.6 molar solution of n-butyllithium in    n-hexane, 11.2 ml of a 1-molar solution of    chlorotris(isopropoxy)titanium in n-hexane, a solution of 4.0 g    FMOC-protected S-α-aminophenylethanol in 20 ml THF and 7.4 ml    piperidine. Chromatography on silica gel (mobile solvent:    ether/n-hexane=1:1 v/v) yielded 2.4 g    (2S,3R,4R,5S)-S_(S)-N(1R)-N-[1-((tert.    butyldimethylsilyl)oxy)methyl-2-methylpropyl]-3-hydroxy-2-phenyl-5-(4-methylphenyl)sulfonimidoylmethyl-2-azabicyclo[3.3.0]octane.-   D) 0.35 g sodium hydrogen carbonate and 1.21 g di-tert. butyl    dicarbonate were added to a solution of 1.58 g of the bicyclic    compound obtained above in 17 ml dioxan and 4 ml water, and the    mixture was stirred for 12 hours. Once the solvent had evaporated    under reduced pressure, the resulting residue was distributed    between 5 ml water and 10 ml ether. The organic phase was separated    and the aqueous phase was extracted twice with ether. Drying of the    combined organic phases over sodium sulfate, evaporation of the    solvent under reduced pressure and chromatography of the remaining    residue on silica gel (mobile solvent: ether/n-hexane 1:1 v/v)    yielded 1.52 g (+)-(2S,3R,4R,5S)-S_(S)-N(1R)-N-[1-((tert.    butyidimethylsilyl)oxy)methyl-2-methylpropyl]-3-hydroxy-2-phenyl-5-(4-methylphenylsulfonimidoylmethyl-(2-aza-N-tert.    butoxycarbonyl)-bicyclo[3.3.0]octane, optical rotation [α]_(D)    ²⁰=+63.2° (c=1.0 in dichloromethane); IR (film)=3473, 1694, 1254,    836 cm⁻¹.-   E) 1.43 g tetrabutylammonium fluoride was added to a solution of    1.52 g of the bicyclic compound protected at the nitrogen obtained    above in 14 ml THF, which solution had been cooled to 0° C., the    mixture was warmed to room temperature after 15 minutes and then    stirred for another 12 hours. The reaction mixture was poured on to    30 ml water which was covered with 20 ml ether. Once the organic    phase had been separated, the aqueous phase was extracted three    times with ether, the organic phase was dried over sodium sulfate    and the solvent was evaporated under reduced pressure.    Chromatography on silica gel (mobile solvent: ethyl    acetate/n-hexane=1:3 v/v) yielded 0.96 g    (+)-(2S,3R,4R,5S)-S_(S)-N(1R)-N-[1-hydroxymethyl-2-methylpropyl]-3-hydroxy-2-phenyl-5-(4-methylphenylsulfonimidoylmethyl-(2-aza-N-tert.    butoxycarbonyl)-bicyclo[3.3.0]octane, optical rotation [α]_(D)    ²⁰=+54.3° (c=1.03 in dichloromethane); IR (film)=3446, 1690, 1239    cm⁻¹.-   F) 3.4 g diiodomethane was added to a suspension of 2.04 g samarium    in 95 ml THF at room temperature, and the mixture was stirred for 60    minutes. Then a solution of 0.955 g of the 5-sulfonimidoyl compound    obtained above in a mixture of 1.7 ml methanol and 3.4 ml THF was    added. The reaction mixture was stirred for 16 hours and then poured    on to 100 ml water. 0.5 N hydrochloric acid solution was added to    the mixture until the suspension had cleared. The phases were    separated and the aqueous phase was extracted twice with ether, the    combined organic phases were dried over sodium sulfate and the    solvent was evaporated under reduced pressure. Chromatography of the    remaining residue on silica gel (mobile solvent: ether/n-hexane=1:3    v/v) yielded 0.43 g of the title compound as a colourless,    solidifying oil (foam), optical rotation [α]_(D) ²⁰=+34.5° (c=1.01    in dichloromethane); IR (film)=3447, 1669 cm⁻¹.

EXAMPLE 4

(−)-(2S,3R,4R,5S)-3-hydroxy-5-methyl-2-phenyl-1-azabicyclo[3.3.0]octane

205 mg (+)-(2S,3R,4R,5S)-3-hydroxy-5-methyl-2-phenyl-1-aza-(N-tert.butoxycarbonyl)-bicyclo[3.3.0]octane (for preparation see Example 3) wasdissolved, under argon atmosphere and with moisture excluded, in amixture consisting of 1.61 ml of a 4.0 M chlorotrimethylsilane solutionin dichloromethane and 4.84 ml of a 4.0 M phenol solution indichloromethane, and the mixture was stirred for 20 minutes at roomtemperature. Then it was poured on to 10 ml of a 10% strength aqueoussodium hydroxide solution, the organic phase was separated, the aqueousphase was extracted twice with 5 ml dichloromethane each time and oncewith 5 ml ether, and the combined organic phases were dried overmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified over silica gel (mobile solvent: ethylacetate/n-hexane 10:1 v/v). 113 mg crystalline title compound wasobtained, melting point=84.5° C., optical rotation [α]_(D) ²⁰=−46.4°(c=1.04 in dichloromethane).

EXAMPLE 5

(+)-(2S,3S,4R,5 S)-3-amino-5-methyl-2-phenyl-1-aza-(N-tert.butoxycarbonyl)-bicyclo[3.3.0]octane

-   A) 241 mg triphenylphosphine and 135 mg phthalimide were added to a    solution of 200 mg    (−)(2S,3R,4R,5S)-3-hydroxy-5-methyl-2-phenyl-1-azabicyclo[3.3.0]octane    in 1.5 ml THF at room temperature under an argon atmosphere and with    moisture excluded. Then 0.14 ml DEAD was added within 2 minutes.    After a reaction time of 10 hours, the solvent was evaporated under    reduced pressure and the residue was taken up in 5 ml ether. Once    undissolved residue had been filtered out and the solvent evaporated    under reduced pressure,    (2S,3S,4R,5S)-5-methyl-2-phenyl-3-phthalimido-1-azabicyclo[3.3.0]octane    was obtained as crude product, which was used for the subsequent    reaction without further purification.-   B) 174 mg of the crude product obtained above was dissolved in 3 ml    dioxan. 220 mg di-tert. butyl dicarbonate and 63 mg sodium hydrogen    carbonate and also 0.5 ml water were added to this receiving    solution and the resulting mixture was stirred for 16 hours at room    temperature. The solvent was evaporated under reduced pressure and    the remaining residue was taken up in water and ether. The phases    were separated and the aqueous phase was extracted twice with 5 ml    ether each time. The combined organic phases were dried over    magnesium sulfate before the solvent was evaporated under reduced    pressure. Chromatography of the remaining residue on silica gel    (mobile solvent: ether/n-hexane 1:3 v/v) yielded 115 mg oily    (2S,3S,4R,5S)-5-methyl-2-phenyl-3-phthalimido-1-aza-(N-tert.    butoxycarbonyl)-bicyclo[3.3.0]-octane.-   C) 400 mg hydrazine hydrate (24% strength) was added to a solution    of 115 mg of the phthalimido-bicyclo[3.3.0]octane obtained above in    2 ml ethanol and the resulting mixture was heated to reflux for 8    hours. The solvent was evaporated under reduced pressure, the    remaining residue was taken up in 10 ml ether and the organic phase    was extracted with 10 ml of a 10% strength aqueous sodium hydroxide    solution. The aqueous phase was extracted twice with 10 ml ether in    each case, and the combined organic phases were dried over magnesium    sulfate. The solvent was evaporated under reduced pressure, and 74    mg crystalline title compound was obtained, melting point=92.1° C.,    [α]_(D) ²⁰=+24.1° (c =1.0 in dichloromethane).

The compounds of Formula I listed in the table below can also beproduced according to the methods given above.

The following abbreviations are used in the table:

Absolute config. at C-atom No. Ex. No. R¹ R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ R⁹ 2 2a 34 6 Y n Mp [° C.] [α]₂₀ ^(D)  6 N.N.  7 H H H H — — H Bn BOC S — R — R O0 108.5 −37.7  8 H H H H — — H i-Bu BOC S — R — R O 0 Oil +28.2  9 H H HH — — H TBOM BOC S — R — R O 0 115.7 +24.5 10 H H H CH₃ — — H Bn BOC S —R R R O 0 127.8 −37.3 11 H H H CH₃ — — H TBOM BOC S — R R R O 0 Oil+14.8 12 H H H H — — H Bn BOC S — S — S O 0 107.7 +6.5 13 H H H H — — Hi-Bu BOC S — S — S O 0 Oil −37.3 14 H H H H — — H TBOM BOC S — S — S O 0 93.1 +1.8 15 H H H CH₃ — — H Bn BOC S — S S S O 0  91.0 +26.7 16 H H HCH₃ — — H i-Bu BOC S — R R R O 0  97.0 −20.0 17 H H H CH₃ — — H TBOM BOCS — S R S O 0 187.2 −20.8 18 H H —(CH₂)₃— — — H Bn BOC S — R R S O 0136.7 +8.2 19 H H —(CH₂)₃— — — H Bn H S — R R S O 0 117.2 −60.7 20 H H—(CH₂)₃— H H H H H — — S R S O 1 21 H H —(CH₂)₄— H H H H H — — S R S O 122 H H —(CH₂)₃— ═CH—CH═CH—CH═ H — — R R S O 1 23 H H —(CH₂)₃— — — H BnBOC S — S S S NH 0  94.6 +48.9 24 H H —(CH₂)₃— — — H Bn H S — S S S NH 0HCl-Salt (Z.) 25 H H —(CH₂)₃— H H H H BOC — — S R S O 1 Oil −17.7 26 H H—(CH₂)₄— H H H H BOC — — S R S O 1 Oil −19.8 i-Bu = isobutyl Bn = benzylBOC = tert. butoxycarbonyl TBOM = tert. butoxymethyl Ph = phenyl Z. =decomposition upon heating N.N. = entry not noted

1. A process for stereochemically controlled production of a compoundcorresponding to formula I:

wherein the R¹R²CH group in the 5-position of the cyclic parentstructure and the hydroxy group in the 3-position of the cyclic parentstructure are each in the trans position relative to each other andwherein the substituent R⁴ in the 4-position and the hydroxy group inthe 3-position of the cyclic parent structure are each in the cisposition relative to each other, and wherein n is 0 or 1, R¹ ishydrogen; R² is hydrogen; R³ is hydrogen, and R⁴ is hydrogen or loweralkyl, or R³ and R⁴ also together are a C₃-C₆-alkylene chain optionallycontaining 1 to 3 double bonds or together form the7,7-dimethylbicyclo[3.1.1]heptyl-system R⁵ is hydrogen or lower alkyl,and R⁶ is hydrogen, and R⁷ is hydrogen, and R⁸ is hydrogen; a monocyclicor bicyclic ring system selected from the group consisting ofcyclopropyl, cyclopentyl cyclohexyl, phenyl, p-bromophenyl and3-indolyl; lower alkyl; phenyl-lower alkyl or lower-alkoxy lower alkyl,or R⁶ and R⁷ also together may form a bond, and R⁵ and R⁸, together withthe carbon atoms to which they are bonded, may form an aromatic C₆-ringsystem, R⁹ is hydrogen; lower alkyl; phenyl-lower alkyl optionallysubstituted one to three times in the phenyl ring by lower alkyl, lowerhaloalkyl, lower alkoxy or lower haloalkoxy; or an amino protectinggroup, or R⁸ and R⁹ also together may form a C₃-C₄-alkylene chain, and Yis oxygen or an acid addition salt thereof, wherein any reactive groupswhich may be present in said compound of Formula I may be blocked bysuitable protecting groups, said process comprising the steps of: a)reacting a compound corresponding to formula II:

wherein R³ and R⁴ have the above meanings, R¹⁰¹ has the meaning givenabove for R¹ Ar represents phenyl optionally substituted one to threetimes by lower alkyl, R¹⁰ is lower alkyl, or phenyl optionallysubstituted once in the phenyl ring by lower alkyl or by hydroxyprotected with a suitable protecting group, or phenyl-lower alkyloptionally substituted once in the phenyl ring by lower alkyl, and R¹¹⁰¹stands for a silyl protecting group, successively with (i) a base forthe deprotonation thereof, (ii) an organometallic reagent correspondingto the formula VII:XM²(OR¹²)₃  VII wherein X is halogen, M² is a tetravalent transitionmetal, and R¹² is lower alkyl, phenyl or phenyl-lower alkyl, and (iii) astereoisomer of a compound of the general formula VIII:

wherein R⁵, R⁶, R⁷ and n have the above meanings, R⁸⁰¹ has the meaningof R⁸, with any reactive groups, if necessary, being blocked bybase-stable protecting groups, R⁹⁰¹ is hydrogen or together with R⁸⁰¹forms a C₃-C₄-alkylene chain, and R¹³ is a base-labile amino protectinggroup which when cleaved leaves behind a nitrogen nucleophile, to form astereoisomer of a compound corresponding to the formula IX:

wherein R¹⁰¹, R³, R⁴, R⁵, R⁶, R⁷, R⁸⁰¹, R⁹⁰¹, R¹⁰, R¹¹⁰¹, R¹², R¹³, n,Ar and M2 have the above meanings, and b) converting the compound ofFormula IX by treatment with a base reagent for removing the group R¹³,into a compound corresponding to formula Xa:

wherein R¹⁰¹, R³, R⁴, R⁵, R⁶, R⁷, R⁸⁰¹, R⁹⁰¹, R¹⁰, n and Ar have theabove meanings, and R¹¹ is hydrogen or a silyl protecting group, and ifR⁹⁰¹ is hydrogen, blocking the nitrogen atom in the cyclic parentstructure of the resulting compound of Formula Xa with a base-stableprotecting group, and cleaving off any silyl protecting group R¹¹ whichmay still be present; and c) for the production of a compoundcorresponding to formula Ia:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸⁰¹ and n have the above meanings,and R⁹⁰² stands for a base-stable protecting group or, together withR⁸⁰¹, for a C₃-C₄-alkylene chain, reacting a compound corresponding toformula Xa or a compound produced by cleaving off the silyl protectinggroup R11 with samarium (II) iodide for the reductive cleavage of thesulfonimidoyl-alkyl bond, and optionally cleaving off any protectinggroups in compounds of Formula Ia, and optionally reacting theoptionally released NH group in the 1-position of the cyclic parentstructure with a reagent capable of N-alkylation or a reagent capable ofamide formation or blocking the released NH group with an aminoprotecting group, thereby obtaining said compound corresponding toFormula I.
 2. A process for stereochemically controlled production of acompound corresponding to formula I:

wherein the R¹R²CH group in the 5-position of the cyclic parentstructure and the hydroxy group in the 3-position of the cyclic parentstructure are each in the trans position relative to each other andwherein the substituent R⁴ in the 4-position and the hydroxy group inthe 3-position of the cyclic parent structure are each in the cisposition relative to each other, and wherein n is 0 or 1, R¹ ishydrogen; R² is hydrogen; R³ is hydrogen, and R⁴ is hydrogen or loweralkyl, or R³ and R⁴ also together are a C₃-C₆-alkylene chain optionallycontaining 1 to 3 double bonds or together form the7,7-dimethylbicyclo[3.1.1]heptyl-system R⁵ is hydrogen or lower alkyl,and R⁶ is hydrogen, and R⁷ is hydrogen, and R⁸ is hydrogen; a monocyclicor bicyclic ring system selected from the group consisting ofcyclopropyl, cyclopentyl cyclohexyl, phenyl, p-bromophenyl and3-indolyl; lower alkyl; phenyl-lower alkyl or lower-alkoxy lower alkyl,or R⁶ and R⁷ also together may form a bond, and R⁵ and R⁸, together withthe carbon atoms to which they are bonded, may form an aromatic C⁶-ringsystem, R⁹ is lower alkyl: phenyl-lower alkyl optionally substituted oneto three times in the phenyl ring by lower alkyl, lower haloalkyl, loweralkoxy or lower haloalkoxy; or an amino protecting group, or R⁸ and R⁹also together may form a C₃-C₄-alkylene chain, and Y is oxygen or anacid addition salt thereof, wherein any reactive groups which may bepresent in said compound of Formula I may be blocked by suitableprotecting groups, said process comprising the steps of: a) reacting acompound corresponding to formula II:

wherein R³ and R⁴ have the above meanings, R¹⁰¹ has the meaning givenabove for R¹ Ar represents phenyl optionally substituted one to threetimes by lower alkyl, R¹⁰ is lower alkyl, or phenyl optionallysubstituted once in the phenyl ring by lower alkyl or by hydroxyprotected with a suitable protecting group, or phenyl-lower alkyloptionally substituted once in the phenyl ring by lower alkyl, and R¹¹⁰¹stands for a silyl protecting group, successively with (i) a base forthe deprotonation thereof, (ii) an organometallic reagent correspondingto the formula VII:XM²(OR¹²)₃  VII wherein X is halogen, M² is a tetravalent transitionmetal, and R¹² is lower alkyl, phenyl or phenyl-lower alkyl, and (iii) astereoisomer of a compound of the general formula VIII:

wherein R⁵, R⁶, R⁷ and n have the above meanings, R⁸⁰¹ has the meaningof R⁸, with any reactive groups, if necessary, being blocked bybase-stable protecting groups, R⁹⁰¹ together with R⁸⁰¹ forms aC₃-C₄-alkylene chain, and R¹³ is a base-labile amino protecting groupwhich when cleaved leaves behind a nitrogen nucleophile, to form astereoisomer of a compound corresponding to the formula IX:

wherein R¹⁰¹, R³, R⁴, R⁵, R⁶, R⁷, R⁸⁰¹, R⁹⁰¹, R¹⁰, R¹¹⁰¹, R¹², R¹³, n,Ar and M2 have the above meanings, and c) converting the compound ofFormula IX by treatment with a base reagent for removing the group R¹³,into a compound corresponding to formula Xa:

wherein R¹⁰¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸⁰¹, R⁹⁰¹, R¹⁰, n and Ar have theabove meanings, and R¹¹ is hydrogen or a silyl protecting group, andcleaving off any silyl protecting group R¹¹ which may still be present;and c) for the production of a compound corresponding to formula Ia:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸⁰¹ and n have the above meanings,and R⁹⁰² stands for a base-stable protecting group or, together withR⁸⁰¹, for a C₃-C₄-alkylene chain, reacting a compound corresponding toformula Xa or a compound produced by cleaving off the silyl protectinggroup R11 with samarium (II) iodide for the reductive cleavage of thesulfonimidoyl-alkyl bond, and (a) cleaving any protecting groups whichmay be present, and (b) reacting any free NH group in the 1-position ofthe cyclic parent structure with (i) a reagent capable of N-alkylation,or (ii) a reagent capable of amide formation, or (iii) a reagent whichblocks the free NH group with an amino protecting group.
 3. A processaccording to claim 1, wherein said base-labile amino protecting group isa fluoren-9-yl-methyloxy-carbonyl radical.
 4. A process according toclaim 1, wherein the base reagent is piperidine.
 5. A process accordingto claim 1, wherein toluene is used as a solvent in step a).
 6. Aprocess according to claim 1, wherein R⁴ is other than hydrogen in eachof the compounds corresponding to formulas I, Ia, II, IX and Xa.
 7. Aprocess according to claim 1, wherein R¹¹⁰¹ is a tert.butyl-dimethylsilyl protecting group or a trimethylsilyl protectinggroup.
 8. A compound corresponding to formula Xa:

wherein n is 0 or 1, R³ is hydrogen, and R⁴ is hydrogen or lower alkylor R³ and R⁴ also together are a C₃-C₆-alkylene chain optionallycontaining 1 to 3 double bonds or together form the 7,7-dimethyl[3.1.1]heptyl-system R⁵ is hydrogen or lower alkyl, and R⁶ is hydrogen,and R⁷ is hydrogen, R¹⁰ is lower alkyl, or phenyl optionally substitutedonce in the phenyl ring by lower alkyl or by hydroxy protected with asuitable protecting group, or phenyl-lower alkyl optionally substitutedonce in the phenyl ring by lower alkyl, R¹¹ is hydrogen or a silylprotecting group, R¹⁰¹ is hydrogen; R⁸⁰¹ is hydrogen; a monocyclic orbicyclic ring system selected from the group consisting of cyclopropyl,cyclopentyl, cyclohexyl, phenyl, p-bromophenyl and 3-indolyl; loweralkyl; phenyl-lower alkyl or lower-alkoxy lower alkyl, with the provisothat when n=0, R⁸⁰¹ is hydrogen, a monocyclic or bicyclic ring systemselected from the group consisting of cyclopropyl, cyclopentyl,cyclohexyl, phenyl, p-bromophenyl and 3-indolyl; lower alkyl; orlower-alkoxy lower alkyl, or R⁶ and R⁷ also together may form a bond,and R⁵ and R⁸⁰¹, together with the carbon atoms to which they arebonded, may form an aromatic C₆-ring system R⁹⁰¹ is hydrogen or togetherwith R⁸⁰¹ forms a C₃-C₄-alkylene chain, and Ar represents phenyloptionally substituted one to three times by lower alkyl, wherein thesulfur-containing substituent in the 5-position and the hydroxy group inthe 3-position of the cyclic parent structure are in the trans positionrelative to each other, and wherein the substituent R⁴ in the 4-positionand the hydroxy group in the 3-position of the cyclic parent structureare in the cis position relative to each other, or a compound obtainableby removal of any protecting groups which may be present in saidcompound corresponding to formula Xa, or an acid addition salt formedwith a free amino group which may be present in said compoundcorresponding to formula Xa.
 9. A compound according to claim 8, whereinthe cyclic structure of formula Xa contains a secondary nitrogen atomprotected by a tert. butoxycarbonyl protecting group.
 10. A compoundaccording to claim 8, wherein R⁸⁰¹ and R⁹⁰¹ together form aC₃-C₄-alkylene chain.
 11. A method of reductive desulfurisation of analkyl-sulfonimidoyl compound corresponding to formula Xa of claim 8,wherein R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹¹, R¹⁰¹, R⁸⁰¹, R⁹⁰¹ and Ar have themeanings given in claim 8, said method comprising reducing saidalkyl-sulfonimidoyl compound with samarium (II) iodide.
 12. A processfor stereochemically controlled production of an azacyclic compoundaccording to claim 1, wherein the compound of formula II is producedfrom a compound selected from the group consisting of(RS)-4(S)-isopropyl-2-p-toluoyl-4,5-dihydro[1,26,3]oxathiazol-2-oxide,(Ss)-4(S)-isopropyl-2-p-toluoyl-4,5-dihydro[1,26,3]oxathiazol-2-oxide,(Rs)-4(R)-isopropyl-2-p-toluoyl-4,5-dihydro[1,26,3]oxathiazol-2-oxide,and(SS)-4(R)-isopropyl-2-p-toluoyl-4,5-dihydro[1,26,3]-oxathiazol-2-oxide.13. A process for stereochemically controlled production of an azacycliccompound according to claim 1, wherein the compound of formula II isproduced from[SS,N(1S)]-N-[1-[[tert.-butyldimethylsilyl)-oxy]methyl]-2-methylpropyl]-S-methyl-S-(4-methylphenyl)-sulfoximideor[RS,N(1R)]-N-[1-[[tert.-butyldimethylsilyl)oxy]-methyl]-2-methylpropyl]-S-methyl-S-(4-methylphenyl)sulfoximide.